L-threo-dihydroxyphenylserine corrects neurochemical abnormalities in a Menkes disease mouse model.
L-threo-dihydroxyphenylserine corrects neurochemical abnormalities in a Menkes disease mouse model.
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DOI：
10.1002/ana.23787
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发表时间：
2013-02
影响因子：
11.2
通讯作者：
Kaler, Stephen G.
中科院分区：
文献类型：
--
作者：
Donsante, Anthony;Sullivan, Patricia;Goldstein, David S.;Brinster, Lauren R.;Kaler, Stephen G.
Menkes病是一种致命的婴儿期神经退行性疾病，由铜转运ATP酶基因ATP 7A突变引起。在其多种细胞任务中，ATP 7A将铜转移到高尔基体网络或分泌颗粒的内腔内的多巴胺-β-羟化酶（DBH），催化多巴胺转化为去甲肾上腺素。在一个成熟的门克斯病（斑点状）小鼠模型中，我们测试了全身给予L-苏型-二羟基苯基丝氨酸（L-DOPS）（一种成功用于治疗常染色体隐性去甲肾上腺素缺乏症的药物）是否会改善大脑神经化学异常和神经病理学。在8、10和12日龄时，野生型和mo-br小鼠接受腹膜内注射200μg/g体重的L-DOPS或模拟溶液。最后一次注射后5小时，将小鼠安乐死并取出大脑。我们通过高效液相色谱电化学检测法测定了DBH对儿茶酚胺代谢物的影响，并评估了脑组织病理学。与模拟治疗对照组相比，腹腔注射L-DOPS的mo-br小鼠的脑去甲肾上腺素（P<0.001）及其脱氨代谢物二羟苯乙二醇（DHPG，P<0.05）显着增加。儿茶酚胺生物合成途径中的非β-羟基化代谢物二羟基苯乙酸与β-羟基化代谢物二羟基苯乙二醇的比率与先前脑定向ATP 7A基因治疗获得的结果相当（P<0.01）。然而，L-DOPS治疗并没有像基因治疗那样阻止全脑病变或改善躯体生长。我们得出结论：1）L-DOPS穿过血脑屏障，并纠正脑神经化学异常，2）去甲肾上腺素缺乏不是导致神经变性的原因，在mo-br小鼠，和3）L-DOPS治疗可能改善去甲肾上腺素功能减退在Menkes病。
Menkes disease is a lethal neurodegenerative disorder of infancy caused by mutations in a copper-transporting ATPase gene, ATP7A. Among its multiple cellular tasks, ATP7A transfers copper to dopamine-beta-hydroxylase (DBH) within the lumen of the Golgi network or secretory granules, catalyzing the conversion of dopamine to norepinephrine. In a well-established mouse model of Menkes disease, mottled-brindled, we tested whether systemic administration of L-threo-dihydroxyphenylserine (L-DOPS), a drug used successfully to treat autosomal recessive norepinephrine deficiency, would improve brain neurochemical abnormalities and neuropathology. At 8, 10, and 12 days of age, wild type and mo-br mice received intraperi-toneal injections of 200μg/g body weight of L-DOPS, or mock solution. Five hours after the final injection, the mice were euthanized and brains removed. We measured catecholamine metabolites affected by DBH via high-performance liquid chromatography with electrochemical detection, and assessed brain histopathology. Compared to mock-treated controls, mo-br mice that received intraperitoneal L-DOPS showed significant increases in brain norepinephrine (P<0.001) and its deaminated metabolite, dihydroxyphenylglycol (DHPG, P<0.05). The ratio of a non-beta-hydroxylated metabolite in the catecholamine biosynthetic pathway, dihydroxyphenylacetic acid, to the beta-hydroxylated metabolite, dihydroxyphenylglycol, improved equivalently to results obtained previously with brain-directed ATP7A gene therapy (P<0.01). However, L-DOPS treatment did not arrest global brain pathology or improve somatic growth, as gene therapy had. We conclude that 1) L-DOPS crosses the blood-brain barrier in mo-br mice and corrects brain neurochemical abnormalities, 2) norepinephrine deficiency is not the cause of neurodegeneration in mo-br mice, and 3) L-DOPS treatment may ameliorate noradrenergic hypofunction in Menkes disease.
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